Current biomarkers are not sufficiently robust for predicting efficacy of chemotherapy in patients with colorectal cancer. Recent progress suggests that one promising biomarker may be PTTG1 (pituitary tumor transforming gene). However, there is a fundamental gap in understanding how PTTG1 regulates cancer treatment outcome. The long-term goal is to understand PTTG1 functions in mediating GH/IGF1 axis in colorectal cancer development and treatment. The primary objective of the proposed research is to identify PTTG1 signaling pathways in regulating colorectal cancer cell response to anti-neoplastic drugs. The central hypothesis is that transcriptional targets of PTTG1 regulate drug-induced apoptosis. Here the candidate propose to test this hypothesis by: 1) identifying the specific cellular death programs mediated by PTTG1;2) identifying PTTG1 target genes involved in regulating cellular responses to anti-neoplastic drugs;3) determining whether colon tumor devoid of PTTG1 are more sensitive to anti-neoplastic drugs. The applicant is a PhD who strives to become an independent scientist focused on translational cancer research in endocrine-related cancer. His current research is to investigate the role of PTTG1 in mediating endocrine pathway functions. He proposes a carefully mentored, comprehensive training program that will facilitate the candidate's transition to independence. The candidate's milestone-driven training plan centers on: 1) didactic coursework;2) receiving academic and research training using the proposed studies as a vehicle;3) comprehensive training in research ethics;4) developing an area of research related to yet distinct from that of the mentors;and 5) learning the practical aspects of becoming a successful independent researcher. The candidate will use this training to obtain an independent faculty position and further NIH research funding. A multidisciplinary mentoring team has been assembled that has the scope and breadth of expertise and experience needed to advice him to obtain definitive outcomes. Dr. Shlomo Melmed, a Professor of Medicine and widely known for his research on PTTG1 and endocrine pathways, will be the mentor. Dr. H. Phillip Koeffler will be the co-mentor for his expertise in anti-cancer drug research, rodent colorectal cancer models, and cancer metastasis. Both mentors have a long history of successful training of research personnel into independently-funded academic positions. Dr. Robert M. Hoffman, a pioneering expert in metastatic colorectal cancer models and GFP-based metastasis imaging, will be the consultant. A Scientific Advisory Committee will consist of: Keith L. Black, MD, for his expertise in anti-cancer drug and cancer metastasis;Jerome I. Rotter, MD, for his expertise in human genetic research and biomarker discovery and validation;Basil Rapoport, MD, for his expertise in molecular medicine and animal studies. The applicant will be mentored and advised by experts in basic and translational cancer research, anti-cancer drug investigation, genetics and endocrinology.
Our proposed study will provide the knowledge needed to apply PTTG1 in novel strategies to predict anti- neoplastic drug treatment efficacy in colorectal cancer. Once such strategies become available, we may be able to prospectively match colorectal cancer patients with the most efficacious therapeutic regimens, thus in effect personalizing chemotherapy to the patient. Moreover, to increase responsiveness to an anti-neoplastic drug, PTTG1 pathways could be blocked.
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